A role for tumor suppressor Hic1 in cerebellar development and medulloblastoma

Medulloblastoma (MB) is a primitive neuroectodermal tumor primarily of childhood, which commonly manifests activation of Hedgehog (Hh) signaling. However, mutations in the tumor suppressor PATCHED ( PTCH), a critical negative regulator of Hh signaling, are found in less than 20% of sporadic cases. In the search for other tumor suppressors, interest has focused on the deletion events at the 17p13.3 locus, the commonest genetic defect in medulloblastoma. This chromosomal region contains HYPERMETHYLATED IN CANCER 1 (HIC1), a transcriptional repressor that is a frequent target of epigenetic gene silencing in medulloblastoma. Though deletion and/or hypermethylation of Hypermethylated in Cancer-1 ( HIC1), a POZ domain transcriptional repressor, are the most frequent genetic event in MB, the function of HIC1 in neural development and tumor suppression is unknown. This work demonstrates that Hic1 is an important tumor suppressor in MB using a novel mouse model, and also shows that Hic1 may play a critical role in normal cerebellar development. Compared to mice heterozygous for a mutation in Ptch1 , compound Ptch1/Hic1 heterozygous mutants demonstrate a marked increase in the incidence of MB. Ptch1/Hic1 tumors manifest hedgehog pathway activation as well as silencing of the wild type Hic1 allele by promoter hypermethylation. Microarray expression analysis in human MB using a HIC1 expressing adenovirus identifies ATONAL homolog 1 (ATOH1), a proneural transcription factor essential for cerebellar development, as a candidate transcriptional target of HIC1. Hic1 protein has been shown to interact directly with Atoh1 by chromatin immunoprecipitation, and its expression results in a reduction of Atoh1 expression. We conclude that Hic1 gene silencing genetically interacts with Ptch1 mutation to promote the formation of MB. Given that Atoh1 is also a putative target of hedgehog signaling, we conclude that the Hic1 and Ptch1 tumor suppressors cooperate to silence Atoh1 expression during a critical phase in GCP differentiation in which malignant transformation may lead to medulloblastoma.